Fluorous tagging compounds and methods of increasing the fluorous nature of compounds

ABSTRACT

A method of increasing the fluorous nature of a compound includes the step of reacting the compound with at least one second compound having the formula: 
                         
wherein Rf is a fluorous group, Rs is a spacer group, d is 1 or 0, m is 1, 2 or 3, Ra is an alkyl group and X is a suitable leaving group. A compound has the formula:
 
                         
wherein Rf is a fluorous group, n is an integer between 0 and 6, m is 1, 2 or 3, Ra is an alkyl group and X is a leaving group.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 09/565,087, filed May 5, 2000, now U.S. Pat. No. 6,825,043 thedisclosure of which is incorporate herein by reference.

FIELD OF THE INVENTION

The present invention relates to fluorous tagging compounds and tomethods of increasing the fluorous nature of compounds.

BACKGROUND OF THE INVENTION

Organic chemists are typically trained that organic compounds have to besynthesized as pure substances through well-planned reactions andscrupulous separation. In fields such as drug discovery, catalyst designand new material development, however, tens of thousands of organiccompounds must be synthesized and tested to discover a few active ones.In the pharmaceutical industry, for example, synthesizing such a largenumber of compounds in the traditional way is too slow compared to therapid emergence of new biological targets. A major factor limiting theproductivity of orthodox solution (liquid) phase organic synthesis isthe tedious separation process for the purification of products. Highthroughput organic synthesis, therefore, preferably integrates organicreactions with rapid purification/separation procedures.

Recently, fluorous synthetic and separation techniques have attractedthe interest of organic chemists. In fluorous synthetic techniques,reaction components are typically attached to fluorous groups such asperfluoroalkyl groups to facilitate the separation of products. Ingeneral, fluorous-tagged molecules partition preferentially into afluorous phase while non-tagged ones partition into an organic phase.Although fluorous synthetic and/or separation techniques are promising,such techniques are currently limited by a lack of availability ofsuitable fluorous tags.

It is thus very desirable to develop fluorous tagging compounds andmethods of increasing the fluorous nature of compounds.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method of increasing thefluorous nature of a compound. The method includes the step of reactingthe compound with at least one second compound having the formula:

wherein Rf is a fluorous group (for example, a fluoroalkyl group, afluorinated ether or another highly fluorinated group), Rs is a spacergroup, d is 1 or 0 (that is, Rs may be present or absent), m is 1, 2 or3, Ra is an alkyl group and X is a suitable leaving group. Suitableleaving groups include, but are not limited to, a halide (F, Cl, Br orI), —N₃, CN, RO—, NH₂O—, NHRO—, NR₂O—, RCO₂—, ROCO₂—, RNCO₂—, RS—,RC(S)O—, RCS₂—, RSC(O)S—, RSCS₂—RSCO₂—, ROC(S)O—, ROCS₂—, RSO₂—, RSO₃—,ROSO₂—, ROSO₃—, RPO₃—, ROPO₃—, an N-imidazolyl group, an N-triazolylgroup, an N-benzotriazolyl group, a benzotriazolyloxy group, animidazolyloxy group, an N-imidazolinone group, an N-imidazolone group,an N-imidazolinethione group, an N-imidazolinthione group, anN-succinimidyl group, an N-phthalimidyl group, an N-succinimidyloxygroup, an N-phthalimidyloxy group, —ON═C(CN)R, or a 2-pyridyloxy group.R is preferably an alkyl group or an aryl group.

The terms “alkyl”, “aryl” and other groups refer generally to bothunsubstituted and substituted groups unless specified to the contrary.Unless otherwise specified, alkyl groups are hydrocarbon groups and arepreferably C₁-C₁₅ (that is, having 1 to 15 carbon atoms) alkyl groups,and more preferably C₁-C₁₀ alkyl groups, and can be branched orunbranched, acyclic or cyclic. The above definition of an alkyl groupand other definitions apply also when the group is a substituent onanother group. The term “aryl” refers to phenyl (Ph) or napthyl,substituted or unsubstituted. The terms “alkylene” refers to bivalentforms of alkyl.

The groups set forth above, can be substituted with a wide variety ofsubstituents. For example, alkyl groups may preferably be substitutedwith a group or groups including, but not limited to, halide(s).Preferably, halide constituents are F and/or Cl. Aryl groups maypreferably be substituted with a group or groups including, but notlimited to, halide(s), alkyl group(s), a cyano group(s) and nitrogroup(s). As used herein, the terms “halide” or “halo” refer to fluoro,chloro, bromo and iodo. Preferred halide substituents are F and Cl.

The resulting fluorous “tagged” compound can be used in a variety offluorous reaction and/or separation techniques. Such fluorous reactionand separation techniques are disclosed, for example, in U.S. Pat. Nos.5,859,247 and 5,777,121 and U.S. patent application Ser. No. 09/506,779,assigned to the assignee of the present invention, the disclosures ofwhich are incorporated herein by reference.

Preferably, the molecular weight of the fluorous tag of the presentinvention does not exceed about 2,500. More preferably, the molecularweight does not exceed about 2,000. Even more preferably the molecularweight does not exceed about 1,750. Compounds may bear more than onefluorous tag of the present invention.

In another aspect, the present invention provides a compound (a fluoroustagging compound) having the formula:

wherein Rf is a fluorous group (for example, a fluoroalkyl group, afluorinated ether or another highly fluorinated group), n is an integerbetween 0 and 6, m is 1, 2 or 3, Ra is an alkyl group and X is a leavinggroup. Ra is preferably C₁-C₆ alkyl group.

As used herein, the term “fluorous”, when used in connection with anorganic (carbon-containing) molecule, moiety or group, refers generallyto an organic molecule, moiety or group having a domain or a portionthereof rich in carbon-fluorine bonds (for example, fluorocarbons orperfluorocarbons, fluorohydrocarbons, fluorinated ethers and fluorinatedamines). The term “fluorous compound,” thus refers generally to acompound comprising a portion rich in carbon-fluorine bonds. As usedherein, the term “perfluorocarbons” refers generally to organiccompounds in which all hydrogen atoms bonded to carbon atoms have beenreplaced by fluorine atoms. The terms “fluorohydrocarbons” and“hydrofluorocarbons” include organic compounds in which at least onehydrogen atom bonded to a carbon atom has been replaced by a fluorineatom. A few examples of suitable fluorous groups Rf for use in thepresent invention include, but are not limited to, —C₄F₉, —C₆F₁₃,—C₈F₁₇, —C₁₀F₂₁, —C(CF₃)₂C₃F₇, —C₄F₈CF(CF₃)₂, and —CF₂CF₂OCF₂CF₂OCF₃.

As used herein, the term “tagging” refers generally to attaching afluorous moiety or group (referred to as a “fluorous tagging moiety” or“tagging group”) to a compound to create a “fluorous tagged compound”.Separation of the tagged compounds of the present invention is achievedby using fluorous separation techniques that are based upon differencesbetween/among the fluorous nature of a mixture of compounds. As usedherein, the term “fluorous separation technique” refers generally to amethod that is used to separate mixtures containing fluorous moleculesor organic molecules bearing fluorous domains or tags from each otherand/or from non-fluorous compounds based predominantly on differences inthe fluorous nature of molecules (for example, size and/or structure ofa fluorous molecule or domain or the absence thereof). Fluorousseparation techniques include but are not limited chromatography oversolid fluorous phases such as fluorocarbon bonded phases or fluorinatedpolymers. See, for example, Danielson, N. D. et al., “Fluoropolymers andFluorocarbon Bonded Phases as Column Packings for LiquidChromatography,” J. Chromat., 544, 187-199 (1991). Examples of suitablefluorocarbon bonded phases include commercial Fluofix® and Fluophase™columns available from Keystone Scientific, Inc. (Bellefonte, Pa.), andFluoroSep™-RP-octyl from ES Industries (Berlin, N.J.). Other fluorousseparation techniques include liquid-liquid based separation methodssuch as liquid-liquid extraction or countercurrent distribution with afluorous solvent and an organic solvent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates synthesis and introduction of fluorous BOC groups.

FIG. 2 illustrates synthesis of a fluorous BOC reagent of the presentinvention and its attachment to an amine and detachment from theresulting amide.

FIG. 3 illustrates recovery of a fluorous BOC compound of the presentinvention.

FIG. 4 illustrates the utility of fluorous BOC compounds of the presentinvention in separating a library of compounds.

FIG. 5 illustrates the structure of several amides generated fromfluorous BOC tagging compounds of the present invention.

FIG. 6 illustrates several products generated by deprotection offluorous BOC protected amines.

FIG. 7 illustrates fluorous BOC groups with different fluorine contentand spacer groups.

FIG. 8 illustrates the synthesis of the 96-compound library that isdescribed in Example 15.

FIG. 9 illustrates the isolated yields of the 96-compound library ofFIG. 8.

DETAILED DESCRIPTION OF THE INVENTION

Carbamates are an important class of protecting group for nitrogen. Forexample, virtually all peptide synthesis schemes rely on carbamateprotecting groups of some sort, and carbamates are commonly used inalkaloid synthesis and other areas. One of the most useful carbamates isthe tert-butyloxycarbonyl group (commonly referred to as the “BOC”group) illustrated below:

In the present invention, a new class of fluorous carbamates referred toherein as fluorous BOC compounds or groups were synthesized after theBOC group. The fluorous tagging groups of the present invention can, forexample, be reacted with nitrogen-bearing groups such as amine groups(—NR¹R²) of compounds to create a fluorous-tagged (or protected)compound.

The fluorous BOC (^(F)BOC) groups of the present invention generally actlike traditional BOC and other carbamate groups to protectnitrogen-based functional groups during organic reactions. Protectinggroups are discussed generally in Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis; 3rd ed.; Wiley-Interscience: NewYork, (1999) and Kocienski, P. “Protecting groups”, Thieme: Stuttgart(1994). However, the fluorous BOC groups of the present invention haveadvantages over other traditional carbamate and other protecting groupsin that they facilitate separation of the ^(F)BOC-protected(fluorous-tagged) products from each other and from non-tagged reactioncomponents. Additionally, the fluorous domain of the fluorous BOC groupsare useful not only for attachment to nitrogen, but also to oxygen,sulfur and other heteroatoms. The resulting ^(F)BOC carbonates,thiocarbamates, etc. serve substantially the same purpose and are usedanalogously to the ^(F)BOC carbamates described in greater detailherein.

The reagents used for the protection of amines with fluorous BOC groupsare generally prepared as shown in FIG. 1. Fluorous alcohols 1a-cbearing one, two or three fluorous chains are readily synthesized, forexample, by nucleophilic addition reactions. Addition of anorganometallic reagent Rf(CH₂)_(n)M (wherein, M is, for example,lithium, magnesium halide, etc. and Rf is a fluorous group) to anappropriate ketone generates an alcohol 1a with one fluorous chain andtwo alkyl groups. Similarly, alcohols with two fluorous chains 1b can begenerated by organometallic addition to esters, acids chlorides orrelated molecules, and alcohols with three fluorous chains 1c can begenerated by nucleophilic additions to carbonate esters, phosgene, orrelated molecules. The alcohols with two and three fluorous chainsprepared by these routes usually contain the same fluorous group, butalcohols, with different fluorous groups can be prepared by severalroutes. For example, addition of Rf¹(CH₂)_(n1)M to an aldehyde followedby oxidation of the resulting secondary alcohol and addition ofRf²(CH₂)_(n2)M results in an alcohol with two different fluorous chains(Rf¹ and Rf²) spaced by alkylene spacers that can be the same ordifferent. A series of fluorous alcohols with different numbers offluorines is useful, for example, in fluorous mixture synthesistechniques. See, U.S. patent application Ser. No. 09/506,779.

Fluorous BOC reagents 3 can be prepared by one of many schemes known tothose skilled in the art for the conversion of standard alcohols toactivated carbamoylating agents. For example, alcohols bearing onefluorous chain and two alkyl groups can react with one of many reagents2, which can be considered as doubly activated derivatives of carbonicacids. In FIG. 1, the leaving group (X) is a part of the molecule thatis cleaved in the substitution reaction. Many different leaving groupssuitable for use in the present invention are known to those skilled inthe art. For the purposes of this invention, leaving groups whoseconjugate acids have a pKa of less than about 18 are preferred. Leavinggroups whose conjugate acids have a pKa of less than about 10 are morepreferred. Even more preferred are leaving groups whose conjugate acidshave a pKa of less than about 5. In a preferred method, the fluorousalcohol 1a is first reacted with the reagent 2 to displace the firstleaving group to give 3. The intermediate BOC reagent 3 may be isolatedprior to reaction with an amine under standard conditions, or it may bereacted directly with the amine in situ without isolation. Either orboth of the acylation reactions may be catalyzed by standard catalystsknown to those skilled in the art. An example on one such acylationcatalyst is 4-dimethylaminopyridine (DMAP). Fluorous BOC reagents withtwo or three fluorous chains are prepared and reacted analogously tothose with one chain.

Reactions and Compounds in the Examples:

The synthesis of a representative fluorous BOC (^(F)BOC) reagent 7 ofthe present invention and its attachment to a typical amine 8 anddetachment from the resulting amide 9 are shown in FIG. 2. Reaction ofperfluorooctylethyl iodide with t-BuLi followed by addition of acetoneand workup and chromatographic purification provided the alcohol 5 in60% yield. Activated reagent 6 was generated according to the literaturemethods set forth in M. Itoh, et. al, Bull. Chem. Soc. Jpn., 50, 718(1977), and then reacted with alcohol 5. Workup and chromatographyprovided the representative ^(F)BOC reagent 7 as a solid. Protection ofamino amide 8 with the ^(F)BOC reagent 7 was accomplished under standardconditions and gave ^(F)BOC derivative 9 in quantitative yield.^(F)BOC-protected 9 could be deprotected to regenerate 8 by treatmentwith neat TFA for 40 min followed by evaporation and vacuum drying toremove the fluorous BOC remnants and other volatile compounds. Thefluorous BOC remnants can also be removed by solid phase extraction overfluorous reverse phase silica gel.

The ability to recover the fluorous BOC component for reuse isdemonstrated by the results of FIG. 3. Coupling of 7 with dimethyl amineprovided 10 in 95% yield. Cleavage of 10 with 30/70 CH₂Cl₂/TFA followedby evaporation provided the trifluoroacetate 11 in 100% yield.Trifluoroacetate 11 was hydrolyzed by treatment with lithium hydroxidein methanol to provide the starting alcohol 5 in 87% yield.

To demonstrate the utility of the fluorous BOC group in facilitatingreaction separation, a 16 compound library of amides was made byparallel synthesis as shown in FIG. 4. Amines 12a-d were reacted withthe ^(F)BOC reagent 7 as in FIG. 2 to give ^(F)BOC protected acids13a-d. Each of the four acids was coupled with amines 14a′-d′ understandard amide formation conditions using1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDI),N-hydroxybenzotriazole (HOBt), and triethylamine (Et₃N). These reactionmixtures were purified by solid phase extraction using a commerciallyavailable semi-preparative Fluofix column. The fluorous tagged productsare readily separated from all non-tagged reaction components. Yieldsand structures for the coupled products 15aa′-dd′ are illustrated inFIG. 5.

To demonstrate the removal of the fluorous BOC group, four of theproducts were heated in 3N HCl/MeOH at 60° C. for 16 h. All the volatileproducts (including the residual fluorous products) were removed byexposure to high vacuum, and then the yields of the final aminehydrochlorides were determined by NMR analysis as described in theExamples. These products are shown in FIG. 6. A second library of eightamines involving the steps of ^(F)BOC protection, amide formation withrapid purification by fluorous solid phase extraction, and removal ofthe ^(F)BOC group with TFA, is also described in Example 15. Theresulting secondary amines were used to make 96 tertiary amines.

The amides shown in FIG. 7 were prepared to demonstrate that otherfluorous BOC groups with different numbers of fluorous chains anddifferent spacer elements could also be used. The syntheses of therespective ^(F)BOC precursors and the amides themselves are described inthe Examples. The retention times of amides 16a-c were then measured onan analytical Fluofix column, eluting with the gradient shown in FIG. 7.The retention times of these amides are all longer than that of amide 9.This is expected because they have more fluorines. Under theseconditions, most non-fluorous tagged organic compounds have retentiontimes at or near the solvent front (approximately 2-3 minutes). Since 9can be separated by fluorous solid phase extraction, it follows that themore strongly retained amides 16a-c will also be separable fromnon-tagged compounds by solid phase extraction.

EXPERIMENTAL EXAMPLES Example 1

Authentic Sample of(3,4-Dihydro-1H-isoquinolin-2-yl)piperidin-4-yl-methanone (8).N-Trifluoroacetyl isonipecotic acid (2.56 g, 11.4 mmol),tetrahydroisoquinoline (1.82 g, 13.7 mmol), EDCI (2.63 g, 13.7 mmol),HOBT (1.85 g, 13.7 mmol) and triethylamine (1.38 g, 13.7 mmol) werestirred in dry dichloromethane (30 mL) at 25° C. for 6 h. The reactionwas quenched with water and the aqueous phase was extracted withdichloromethane. The combined organic phase was dried over MgSO₄ andpurified by column chromatography (40/60 EtOAc/hexanes). The solidobtained was stirred with excess K₂CO₃ in MeOH at 25° C. overnight (16h). After evaporation of MeOH, the residue was partitioned betweendichloromethane and basic water. Evaporation of the organic phase gavepure product as a colorless solid (2.12 g, 76% for two steps). ¹H NMR(CDCl₃) (mixture of two rotamers) δ 7.23-7.16 (m, 4H), 4.73 (s, 1H),0.4.67 (s, 1H), 3.83 (t, J=5.9 Hz, 1H), 3.74 (t, J=5.8 Hz, 1H),3.21-3.16 (m, 2H), 2.92 (t, J=5.7 Hz, 1H), 2.85 (t, J=5.7 Hz, 1H),2.76-2.67 (m, 3H), 2.29 (s, 1H), 1.80-1.73 (m, 4H); ¹³C NMR(CD₃OD-CDCl₃) δ 175.5, 175.3, 135.8, 135.1, 134.0, 133.8, 129.6, 129.3,127.9, 127.6, 127.4, 127.3, 127.0, 48.2, 45.8, 45.4, 44.2, 41.4, 40.2,39.6, 39.5, 30.5, 29.5, 29.4, 29.1; LRMS: m/z (relative intensity), 244(M⁺, 37%), 188 (100%), 132 (74%); HRMS: calcd. for C₁₅H₁₉N₂O 244.1576,found 244.1574. MP: 75-76° C.

Example 2

1,5-Bis(perfluorohexyl)-3-methylpentan-3-ol. A portion of2-perfluorohexylethyl iodide (1.0 mL) was added to a suspension of Mgpowder (0.85 g, 35.0 mmol) in dry diethyl ether (5 mL) under argon. Themixture was sonicated for 30 min. To the resulting suspension, asolution of 2-perfluorohexylethyl iodide (total 7.8 ml, 31.8 mmol) indry diethyl ether (40 mL) was added over 40-60 min. Upon completion ofaddition, the dark mixture was stirred at reflux for 1 h. After coolingdown to room temperature, a solution of ethyl acetate (0.9 mL, 11.1mmol) in diethyl ether (4.0 mL) was added slowly. The mixture wasstirred at room temperature overnight before quenching with saturatedaqueous NH₄Cl. The aqueous phase was extracted with diethyl ether (3×20mL). The ether phase was combined and dried over MgSO₄. Afterevaporation of solvent, the residue was purified by columnchromatography with 5:95 ethyl acetate-hexane. The title compoundobtained was further recrystallized twice from chloroform to givecolorless needles (5.18 g, 79%). ¹H NMR (CDCl₃) δ 2.34-2.10 (m, 4H),1.89-1.68 (m, 4H), 1.28 (s, 3H), 1.17 (s, 1H); ¹³C NMR (CDCl₃) δ 70.5,32.0, 26.2, 25.7 (t); IR (Nujol) 3467, 2923, 1461, 1369, 1244, 1140,1051, 701, 521 cm⁻¹; LRMS m/z: 1491 (50%), 1145 (5%), 723 (42%), 375(100%); HRMS found: C, 29.04%, H, 1.62%. Calcd.: C, 29.28%, 1.64%. MP:57-58° C.

Example 3

O-Bis(perfluorohexylethyl)ethyloxycarbonyloxyiminophenylacetonitrile. Toa sample tube sealed under argon was charged with a solution of phosgenein toluene (0.27 mL, 0.55 mmol) and the solution was cooled to 0° C. Asolution of 2-hydroxyimino-2-phenylacetonitrile (75 mg, 0.51 mmol) anddimethylaniline (70 uL, 0.55 mmol) in THF (0.2 mL) and benzene (0.2 mL)was added dropwise to the ice-cooled solution. The mixture was stirredat 0° C. for 6 h. The mixture was placed in a freezer (−20° C.)overnight before returning to the ice bath. A solution of the alcoholfrom Example 2 (0.39 g, 0.55 mmol) and pyridine (45 uL, 0.55 mmol) inTHF (3.0 mL) was added dropwise. The orange mixture was stirred at 0° C.for 6 h and allowed to warm to room temperature over night. Thesuspension was quenched with water and extracted with diethyl ether. Theorganic phase was dried over MgSO₄. After removal of solvent, theresidue was purified by column chromatography with 5:95 ethylacetate-hexanes to give pure product as a white gum (223 mg, 49%). ¹HNMR (CDCl₃) δ 7.95 (d, J=7.5 Hz, 2H), 7.61 (t, J=7.3 Hz, 1H), 7.51 (t,J=7.7 Hz, 2H), 2.42-2.08 (m, 8H), 1.66 (s, 3H); ¹³C NMR (CDCl₃) δ 149.7,138.7, 133.3, 129.4, 127.6, 108.2, 86.1, 28.8, 25.6 (t), 22.8; IR (thinfilm): 1795, 1450, 1240, 1023, 940, 729 cm⁻¹; FABMS m/z: 910 (M⁺,absent), 867 (M⁺−CO₂, 21%), 721 (100%), 681 (16%).

Example 4

1,7-Bis(perfluorobutyl)-4-methylheptan-4-ol. To a solution of3-perfluorobutylpropyl iodide (688 mg, 1.77 mmol) in a mixture of drydiethyl ether and dry hexane (25 mL, 1:1 v/v) was added ^(t)BuLi (2.2mL, 1.7 M in pentane, 3.74 mmol) at −78° C. The mixture was stirred for1 h during which time the temperature increased to −35° C. After coolingto −78° C., acetyl chloride (57 uL, 0.80 mmol) was added dropwise. Thecooling bath was removed and the reaction mixture was stirred for 1 h.Water was added to quench the reaction. After extraction with ether, theorganic phase was dried over MgSO₄ and evaporated to dryness. The crudeproduct was purified by column chromatography with 5:95 ethylacetate-hexane to give the alcohol as a yellow oil (103 mg, 23%). ¹H NMR(CDCl₃) δ 2.19-2.01 (m, 4H), 1.76-1.68 (m, 4H), 1.67-1.53 (m, 4H), 1.24(s, 3H); ¹³C NMR (CDCl₃) δ 121.8-110.8 (m), 72.4, 41.4, 31.3, 26.7,15.1; LRMS m/z (relative intensity) 551 (M⁺−Me, 15%), 305 (100%); HRMSfound: 551.0676, calcd. for C₁₅H₁₃F₁₈O: 551.0679; IR (thin film): 3147,2975, 1468, 1356, 1206, 880, 720 cm⁻¹.

Example 5

1,7-Bis(perfluorohexyl)-4-methylheptan-4-ol. This compound was preparedby the same procedure as Example 4 but ethyl acetate was used instead ofacetyl chloride. Yield: 68% (white solid). ¹H NMR (CDCl₃) δ 2.13-2.04(m, 4H), 1.76-1.66 (m, 4H), 1.64-1.53 (m, 4H), 1.24 (s, 3H); ¹³C NMR(CDCl₃) δ 122.0-107.0 (m), 72.4, 41.4, 31.4 (t), 26.5, 15.1; ¹⁹F NMR(CDCl₃) δ −81.2 (3F), −114.8 (2F), −122.4 (2F), −123.4 (2F), −124.1(2F), −126.6 (2F); LRMS: m/z (relative intensity) 751 (M⁺−Me, 77%), 709(24%), 405 (100%); HRMS found: 751.0570, calcd. for Cl₁₉H₁₃OF₂₆:751.0566; MP: 46-47° C.

Example 6

4-Perfluorooctyl-2-methylbutan-2-ol (5). This compound was prepared bythe same procedure as Example 4 but acetone was used instead of acetylchloride. Yield: 60% (white solid). ¹H NMR (CDCl₃) δ 2.32-2.14 (m, 2H),1.78-1.73 (m, 2H), 1.29 (s, 6H); ¹³C NMR (CDCl₃) δ 122.4-107.4 (m),69.9, 33.5, 29.4, 26.2 (t); LRMS m/z (relative intensity) 505 (M⁺−H,12%), 491 (M⁺−Me, 100%); HRMS found: 491.0306; calcd. for C₁₂H₈F₁₇O:491.0304. MP: 50-51° C.

Example 7

O-Bis(perfluorobutylpropyl)ethoxycarbonyloxyiminophenylacetontrile. Thiscompound was prepared by the same procedure as Example 3. Yield: 27%(gum). ¹H NMR (CDCl₃) δ 7.95 (d, J=8.1 Hz, 2H), 7.60 (t, J=7.2 Hz, 1H),7.51 (t, J=7.5 Hz, 2H), 2.20-1.91 (m, 8H), 1.79-1.71 (m, 4H), 1.62 (s,3H); ¹³C NMR (CDCl₃) δ 150.0, 138.3, 133.2, 129.4, 127.6, 121.5-114.8(m), 108.4, 88.7, 37.5, 30.8 (t), 23.1, 14.8; LRMS m/z (relativeintensity) 761 (M⁺+Na), 548 (45%), 305 (100%), 287 (90%). IR (thinfilm): 2982, 1795, 1234, 1132, 1022, 878 cm⁻¹.

Example 8a

O-(Perfluorooctylethyl)isopropanoxycarbonyloxyiminophenylacetonitrile(7). This compound was prepared by the same procedure as Example 3.Yield: 61% (orange solid). ¹H NMR (CDCl₃) δ 7.95 (d, J=8.1 Hz, 2H), 7.60(t, J=6.9 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 2.29-2.15 (m, 4H), 1.66 (s,6H); ¹³C NMR (CDCl₃) δ 150.0, 138.3, 133.3, 129.5, 127.9, 127.7, 111.0,85.9, 31.5, 25.7; ¹⁹F NMR (CDCl₃) δ −79.6 (3F), −113.2 (2F), −120.7(6F), −121.5 (2F), −121.9 (2F), −124.9 (2F); LRMS: 634 (16%), 615 (10%),489 (100%); MP: 76-78° C.

Example 8b4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-piperidine-1-carboxylic Acid4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-1,1,-dimethyl-undecylEster

A solution of compound 7 (89 mg, 0.13 mmol) and compound 8 (29 mg, 0.12mmol) in dichloromethane (4 ml) was stirred at room temperature for 2 h.The mixture was evaporated to dryness. The residue was purified bycolumn chromatography (3:1 EtOAc/hexanes) to give compound 9 (93 mg,100%) as a white solid. ¹H NMR (CDCl₃) δ 7.22-7.14 (m, 4H), 4.74 (s,1H), 4.68 (s, 1H), 4.23-4.07 (br, 2H), 3.8 (br, 1H), 3.74 (t, J=2.9 Hz,1H), 2.96-2.74 (m, 5H), 2.22-2.01 (m, 4H), 1.74 (br, 4H), 1.51 (s, 6H);¹³C NMR (CDCl₃) δ 173.4, 173.2, 154.2, 135.3, 133.9, 133.6, 132.6,129.3, 128.5, 127.3, 126.9, 126.8, 126.6, 126.1, 47.5, 44.7, 43.8, 43.3,40.2, 39.1, 38.9, 32.1, 30.0, 28.5, 26.2; LRMS: 776 (M⁺, 15%) 757 (27%),739 (22%), 243 (100%), 188 (60%), 132 (45%); HRMS: calcd. forC₂₉H₂₉N₂O₃F₁₇: 776.1907, found 776.1894. MP: 114-116° C.

Example 9

4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)piperidine-1-carboxylic acid1-perfluorooctylethylisopropyl ester (16a). The fluorous Boc reagentfrom Example 3 (89 mg, 0.13 mmol), the compound in Example 1 (29 mg,0.12 mmol) and triethylamine (20 mg, 20.0 mmol) were mixed in drydichloromethane (4.0 mL) and stirred at room temperature for 2 h. Afterevaporation of solvent, the residue was purified by columnchromatography with 30:70 ethyl acetate-hexane to give pure product as awhite solid. Yield: 93 mg (96%); Rf=0.22 (30:70 ethyl acetate-hexane);¹H NMR (mixture of two rotamers) (CDCl₃) δ 7.22-7.14 (m, 4H), 4.74 (s,1H), 4.68 (s, 1H), 4.23-4.07 (br, 2H), 3.85 (br, 1H), 3.74 (t, J=5.8 Hz,1H), 2.95-2.74 (m, 5H), 2.22-2.05 (m, 4H), 1.74 (br, 4H), 1.52 (s, 6H);¹³C NMR (CDCl₃) δ 173.4, 173.2, 154.2, 135.3, 134.0, 133.6, 132.6,129.3, 128.5, 127.3, 126.9, 126.8, 126.6, 126.1, 122.8-107.3 (m), 79.9,47.5, 44.7, 43.8, 43.3, 40.2, 39.1, 38.9, 32.1, 30.0, 28.5, 26.2; LRMS:m/z (relative intensity) 776 (M⁺, 14%), 757 (M⁺−F, 25%), 739 (M⁺−2F,20%), 489 (11%), 287 (20%), 271 (24%), 243 (100%), 188 (60%), 132 (45%);HRMS calcd. for C₂₉H₂₉N₂O₃F₁₇: 776.1907, found: 776.1894; MP: 115° C.

Example 10

Compound 16b. This compound was prepared by the same procedure asExample 9 with the fluorous Boc reagent from Example 8. Yield: 79%(yellowish oil); ¹H NMR (CDCl₃) δ 7.22-7.14 (m, 4H), 4.74 (s, 1H), 4.68(s, 1H), 4.16 (br, 2H), 3.85 (br, 1H), 3.74 (t, J=5.8 Hz, 1H), 2.95-2.74(m, 5H), 2.18-2.00 (m, 6H), 1.75-1.60 (m, 10H), 1.46 (s, 3H); ¹³C NMR(CDCl₃) δ 173.4, 173.2, 154.2, 135.3, 134.0, 133.7, 132.7, 129.5, 129.0,128.7, 128.2, 127.5, 127.0, 126.7, 126.3, 125.0, 123.3-108.7 (m), 82.7,47.6, 44.7, 43.3, 40.2, 39.0, 38.7, 38.3, 37.9, 31.4, 30.8, 30.3, 30.0,28.5 (t), 24.6, 23.7, 14.9 (t); LRMS: m/z (relative intensity) 835(M⁺−H, 35%), 817 (M⁺−F, 23%), 548 (17%), 287 (77%), 243 (100%), 188(72%), 132 (71%).

Example 11

Compound 16c. This compound was prepared by the same procedure asExample 9 with the fluorous Boc reagent from Example 7. Yield: 100%(white solid); ¹H NMR (CDCl₃) δ 7.22-7.14 (m, 4H), 4.74 (s, 1H), 4.68(s, 1H), 4.23-4.07 (br, 2H), 3.8 (br, 1H), 3.74 (t, J=2.9 Hz, 1H),2.96-2.74 (m, 5H), 2.22-2.01 (m, 4H), 1.74 (br, 4H), 1.51 (s, 6H); ¹³CNMR (CDCl₃) δ 173.4, 173.2, 154.2, 135.3, 133.9, 133.6, 132.6, 129.3,128.5, 127.3, 126.9, 126.8, 126.6, 126.1, 47.5, 44.7, 43.8, 43.3, 40.2,39.1, 38.9, 32.1, 30.0, 28.5, 26.2; LRMS: 776 (M⁺, 15%) 757 (27%), 739(22%), 243 (100%), 188 (60%), 132 (45%); HRMS: calcd. for C₂₉H₂₉N₂O₃F₁₇:776.1907, found 776.1894. MP: 114-116° C.

Example 12

Dimethyl-carbamic acid4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-1,1-dimethylundecylester (10). Dimethylamine (300 uL, 2.0 M in THF, 0.60 mmol) was added toa solution of fluorous Boc reagent 7 (101 mg, 0.15 mmol) in THF. Themixture was stirred at room temperature for 1.5 h. After evaporation ofsolvent, the residue was purified by column chromatography with 10:90ethyl acetate/hexane (Rf=0.18) to give pure product (82 mg, 95%); ¹H NMR(CDCl₃) δ2.87 (s, 6H), 2.24-1.99 (m, 4H), 1.51 (S, 6H); ¹³C NMR (CDCl₃)δ 155.5, 122.0-105.2 (m), 79.4, 35.9, 32.1, 26.0; LRMS: 577 (M+, 9%),558 (M⁺−F, 12%), 489 (45%), 90 (70%), 72 (100%); IR (thin film): 2942,1707, 1454, 1389, 1236, 656 cm⁻¹.

Example 13

Trifluoro-acetic acid4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-1,1-dimethylundecylester (11). Dimethylamine(2-perfluorooctylethyl)isopropyl carbamate 10(251 mg, 0.44 mmol) was stirred with 1:1 CH₂Cl₂/TFA at room temperatureovernight. After evaporation of solvent, the residue was partitionedbetween dichloromethane and aqueous K₂CO₃. The organic phase was driedover MgSO₄ and evaporated to give pure product (262 mg, 100%); ¹H NMR(CDCl₃) δ 2.22-2.08 (m, 4H), 1.63 (s, 6H); ¹⁹F NMR (CDCl₃) δ −74.6 (3F),−79.6 (2F), −113.3 (2F), −120.8 (6F), −121.6 (2F), −122.1 (2F), −125.0(2F). ¹³C NMR (CDCl₃) δ 156.4 (t), 121.5-105.1 (m), 86:7, 31.5, 25.7(t), 25.0; LRMS: m/z (relative intensity) 587 (M⁺−Me, 70%), 489(M⁺−CF₃CO₂, 68%), 155 (82%); HRMS calcd. for C₁₃H₁₀F₁₇: 489.0511, found:489.0504; IR (thin film): 2992, 1784, 1371, 1214 cm⁻¹.

Example 14 Synthesis of the Library in FIGS. 4 and 5

1. Piperidine-1,4-dicarboxylic acidmono-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-1,1-dimethylundecyl)ester(13a). To a solution of fluorous Boc reagent 7 (6.2 g, 9.1 mmol) andtriethylamine (1.01 g, 10.0 mmol) in THF was added a solution ofisonipecotic acid (1.29 g, 10.0 mmol) in water. The mixture was stirredat room temperature overnight. After removal of solvent, the solidresidue as stirred with chloroform (300 mL) and the white solid wasfiltered off. The organic solvent was evaporated and the residue wasrecrystallized from chloroform/hexane to give product (2.3 g). Themother liquid was concentrated and purified by column chromatography.The product (total: 5.24 g, 87%) was obtained as a colorless solid. ¹HNMR (CDCl₃) δ 3.97 (br, 2H), 2.99 (t, J=10.9 Hz, 2H), 2.56-2.48 (m, 1H),2.18-1.91 (m, 6H), 1.72-1.59 (m, 2H), 1.51 (s, 6H); ¹³C NMR (CDCl₃) δ180.1, 154.2, 126.1-106.8 (m), 80.1, 43.5, 42.8, 40.8, 31.8, 27.8, 26.2,25.8; LRMS m/z (relative intensity) 661 (M⁺, 13%), 642 (M⁺−F, 41%); HRMScalcd. for C₂₀H₂₀NO₄F₁₇: 661.1148, found: 661.1146; MP: 140-142° C.

2.3-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-1,1-dimethyl-undecyloxycarbonylamino)propionicacid (13b). This compound was prepared by the same procedure as Example14.1. Yield: 51%. ¹H NMR (CDCl₃) δ 5.08 (br, 1H), 3.42 (q, J=5.7 Hz,2H), 2.61 (t, J=5.6 Hz, 2H), 2.17-2.04 (m, 4H), 1.49 (s, 6H); LRMS m/z(relative intensity) 622 (M⁺+H, 6%), 584 (M⁺−2F, 32%), 562 (74%), 489(51%), 133 (47%), 116 (100%); HRMS: found 622.0874; calcd. forC₁₇H₁₇NO₄F₁₇: 622.0886. MP: 94-95° C.

3.4-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-1,1-dimethyl-undecyloxycarbonylamino)-methyl]benzoicacid (13c). This compound was prepared by the same procedure as Example14.1. Yield: 52%. ¹H NMR (MeOH-d4) δ 7.96 (d, J=8.2 Hz, 2H), 7.36 (d,J=8.2 Hz, 2H), 4.30 (s, 2H), 2.20-2.01 (m, 4H), 1.50 (s, 6H); LRMS m/z(relative intensity) 667 (M⁺−F, 59%), 547 (63%), 489 (54%), 196 (100%),151 (55%). MP: 137-140° C.; HRMS: found: 66.0929; calcd. forC₂₂H₁₇NO₃F₁₇: 666.0937.

4. (2S)-Pyrrolidine-1,2-dicarboxylic acid1-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-1,1-dimethylundecyl)ester(13d). This compound was prepared by the same procedure as Example 14.1.Yield: 47%. ¹H NMR (CDCl₃) δ 4.37-4.22 (m, 1H), 3.55-3.35 (m, 2H),2.26-1.93 (m, 8H), 1.52-1.47 (s, 6H); ¹³C NMR (MeOH-d4) δ176.6, 155.5,120.4-109.2 (m), 81.6, 60.6, 47.8, 32.8, 32.0, 31.1, 27.0, 26.5, 25.3,24.6; LRMS m/z (relative intensity) 646 (M⁺−H, 10%), 628 (M⁺−F, 16%),489 (56%), 114 (100%), 70 (70%); HRMS calcd. for C₁₈H₁₇NO₂F₁₇: 602.0974,found: 602.0988; MP: 75-76° C.

5. General Procedure for the Synthesis of 15. To sixteen vials wereadded acids 13a-d (0.06 mmol), amines 14a′-d′ (0.24 mmol), EDCI (0.09mmol), HOBT (0.09 mmol) and Et₃N (0.09 mmol). Chloroform (0.5 mL) andDMF (0.5 mL) was added to each vial. These sixteen reaction mixtureswere stirred at room temperature for 16 h. After concentration with avacuum centrifuge, each reaction mixture was injected onto a preparativeFluofix™ 1EW 125 column. The column was eluted with 9:1 MeOH—H₂O for 25min and followed by pure MeOH for 20 min. The fractions of products werecollected and evaporated with a vacuum centrifuge to give the sixteencompound library 15aa-15dd′, which was analyzed by ¹H NMR spectroscopy.The isolated yields of the amides are listed in FIG. 5.

15aa′ ¹H NMR (CDCl₃) δ 7.22-7.17 (m, 4H), 4.74 (s, 1H), 4.68 (s, 1H),4.14-4.10 (m, 2H), 3.84 (s, 1H), 3.74 (t, J=5.7 Hz, 1H), 2.95-2.74 (m,4H), 2.24-2.05 (m, 4H), 1.74 (br, 4H), 1.51 (s, 6H).

15ab′ ¹H NMR (CDCl₃) δ 8.54 (d, J=6.0 Hz, 2H), 7.16 (d, J=5.8 Hz, 2H),5.95 (s, 1H), 4.46 (d, J=6.0 Hz, 2H), 4.11 (br, 2H), 2.80 (t, J=11.8 Hz,2H), 2.34-2.28 (m, 5H), 1.71 (br, 4H), 1.51 (s, 6H).

15ac′ ¹H NMR (CDCl₃) δ 6.08 (s, 1H), 4.08 (br, 2H), 3.53-3.49 (m, 1H),3.16-3.11 (m, 2H), 2.81-2.74 (m, 3H), 2.52 (br, 1H), 2.26-2.03 (m, 8H),1.85-1.53 (m, 7H), 1.51 (s, 6H), 1.10 (t, J=7.2 Hz, 3H).

15ad′ ¹H NMR (CDCl₃) δ 7.56-7.43 (m, 4H), 5.85 (t, J=5.4 Hz, 1H), 4.51(d, J=6.0 Hz, 2H), 4.10 (br, 2H), 2.79 (br, 2H), 2.36-2.06 (m, 5H),1.87-1.60 (m, 4H), 1.51 (s, 6H).

15ba′ ¹H NMR (CDCl₃) δ 7.24-7.09 (m, 4H), 5.45 (t, J=5.8 Hz, 1H), 4.74(s, 1H), 4.59 (s, 1H), 3.83 (t, J=6.0 Hz, 1H), 3.65 (t, J=5.9 Hz, 1H),3.50-3.45 (m, 2H), 2.92-2.85 (m, 2H), 2.61-2.58 (m, 2H), 2.22-1.98 (m,4H), 1.56 (s, 6H).

15bb′ ¹H NMR (CDCl₃) δ 8.55 (d, J=5.9 Hz, 2H), 7.17 (d, J=5.8 Hz, 2H),6.35 (s, 1H), 5.29 (s, 1H), 4.46 (d, J=6.0 Hz, 2H), 3.45 (q, J=6.0 Hz,2H), 2.51 (t, J=5.8 Hz, 2H), 2.11-1.98 (m, 4H), 1.46 (s, 6H).

15bc′ ¹H NMR (CDCl₃) δ 6.16 (br, 1H), 5.38 (s, 1H), 4.14 (br, 2H),3.67-3.41 (m, 2H), 3.16-3.12 (m, 2H), 2.79-2.75 (m, 2H), 2.55 (br, 1H),2.42 (br, 1H), 2.24-2.02 (m, 4H), 1.85-1.68 (m, 5H), 1.48 (s, 6H), 1.08(m, 3H).

15bd′ ¹H NMR (CDCl₃) δ 7.56-7.42 (m, 4H), 6.11 (s, 1H), 5.23 (s, 1H),4.50 (d, J=5.9 Hz, 2H), 3.48-3.42 (q, J=6.0 Hz, 2H), 2.48 (t, J=5.9 Hz,2H), 2.22-1.99 (m, 4H), 1.46 (s, 6H).

15ca′ ¹H NMR (CDCl₃) 7.43 (d, J=7.8 Hz, 2H), 7.33 (d, J=7.6 Hz, 2H),7.18-7.01 (m, 4H), 5.0 (br, 1H), 4.94 (br, 1H), 4.59 (br, 1H), 4.37 (m,2H), 3.99 (br, 1H), 3.64 (br, 1H), 2.97-2.87 (br, 2H), 2.20-2.06 (m,4H), 1.53 (s, 6H).

15cb′ ¹H NMR (CD₃OD) δ 8.47 (s, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.39 (d,J=8.0 Hz, 4H), 4.62 (s, 2H), 4.30 (s, 2H), 2.31-2.09 (m, 4H), 1.46 (s,6H).

15cc′ ¹H NMR (CDCl₃) δ 7.74 (d, J=8.1 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H),4.36 (s, 2H), 3.71-3.67 (m, 1H), 3.31-3.25 (m, 2H), 2.82-2.79 (m, 2H),2.28-1.99 (m, 8H), 1.74-1.63 (m, 2H), 1.51 (s, 6H), 1.11 (t, J=7.2 Hz,3H).

15cd′ ¹H NMR (CDCl₃) δ 7.77 (d, J=8.2 Hz, 2H), 7.60-7.41 (m, 4H), 7.34(d, J=7.75 Hz, 2H), 6.48 (s, 1H), 4.98 (s, 1H), 4.71 (d, J=5.8 Hz, 2H),4.36 (m, 2H), 2.36-1.91 (m, 4H), 1.51 (s, 6H).

15da′ ¹H NMR (CDCl₃) δ 7.26-7.11 (m, 4H), 4.83-4.58 (m, 0.3H), 4.10 (m,1H), 3.70-3.56 (m, 3H), 2.91-2.84 (m, 2H), 2.24-1.84 (m, 8H), 1.52 (s,6H).

15db′ ¹H NMR (CDCl₃), δ 8.53 (d, J=4.3 Hz, 2H), 7.43 (s, 1H), 7.17 (d,J=5.7 Hz, 2H), 4.51-4.34 (m, 3H), 3.43-3.36 (m, 2H), 2.40-1.94 (m, 8H),1.40 (s, 6H).

15dc′ ¹H NMR (CDCl₃) δ 6.91 (s, 1H), 6.42 (s, 1H), 4.29-4.18 (m, 1H),3.51-3.40 (m, 3H), 3.13-2.05 (m, 2H), 2.75 (m, 1H), 2.52 (m, 1H),2.26-1.68 (m, 13H), 1.52 (s, 6H), 1.08 (t, J=7.2 Hz, 3H).

15dd′ ¹H NMR (CDCl₃) δ 7.50-7.36 (m, 4H), 4.49-4.23 (m, 4H), 3.49-3.32(m, 2H), 2.41-1.82 (m, 7H), 1.51 (s, 6H).

6. General Procedure for the Deprotection of 15. Amide 15 (0.05 mmol)was heated with 3N HCl/MeOH (1.0 mL) at 65° C. for 16 h. The mixture wasevaporated and dried under high vacuum (˜1 mmHg) for 16 h. The yields ofproducts were determined by ¹H NMR spectroscopy with p-dimethoxybenzeneas an internal standard and are shown in FIG. 6.

Amine from compound 15aa′. ¹H NMR (CDCl₃) δ 7.21-7.13 (m, 4H), 4.73 (s,1H), 4.67 (s, 1H), 3.84 (t, J=5.9 Hz, 1H), 3.75-3.69 (m, 1H), 3.24 (br,2H), 2.95-2.78 (m, 5H), 1.79 (br, 4H).

Amine from compound 15bb′. ¹H NMR (CD₃OD) δ 8.98 (d, J=5.9 Hz, 2H), 8.21(d, J=6.0 Hz, 2H), 4.56 (s, 2H), 3.21 (m, 2H), 2.77-2.73 (m, 2H).

Amine from compound 15cc′. ¹H NMR (CD₃OD) δ 8.01 (d, J=8.1 Hz, 2H), 7.60(d, J=8.1 Hz, 2H), 4.20 (s, 2H), 3.92-3.58 (m, 5H), 3.30-3.15 (m, 2H),2.29-2.02 (m, 4H), 1.41 (t, J=6.9 Hz, 3H).

Amine from compound 15dd′. ¹H NMR (CD₃OD) δ 9.00 (s, 1H), 7.83-7.54 (m,4H), 4.52 (m, 2H), 4.34-4.29 (m, 1H), 3.73 (s, 2H), 3.43-3.31 (m, 1H),2.48-2.42 (m, 1H), 2.11-1.98 (m, 2H).

Example 15

General Procedure for the Synthesis of the Library in FIGS. 8 and 9.Eight vials were charged with a mixture of acid 13a (330 mg, 0.50 mmol),an amine 17{1-8} (2.0 mmol), EDCI (0.70 mmol), HOBT (0.70 mmol) andtriethylamine (0.70 mmol) in chloroform/DMF. The reaction mixtures werestirred at room temperature overnight (16 h) and quenched with water.The organic phase was collected and evaporated with a vacuum centrifuge.These residues were charged onto eight short columns packed withfluorous reverse phase silica gel (5 g, bonded phase—Si(Me)₂CH₂CH₂C₆F₁₃). Each column was eluted with 80:20 MeOH—H₂O (15 mL)followed by MeOH (5 mL) and diethyl ether (20 mL). The combined MeOH andether fractions were evaporated to dryness with a vacuum centrifuge togive library 18{1-8}. A mixture of dichloromethane and TFA (1:1, 5 mL)was added to each of these amides 18. The reaction mixtures were stirredat room temperature for 2.5 h. After removal of dichloromethane and TFA,stock solutions of the residues 19{1-8} were prepared. Each of theseeight solutions in DMF was added to an array of twelve halides 20{1-12}in the presence of diisopropylethylamine (0.5 mmol). These 96 reactionmixtures were heated at 50° C. for 48 h. After concentration, themixtures were purified with a PrepLCMS system. In 89 out of 96reactions, the desired products were detected by LC-MS and isolated inyields from 5 to 100% (FIG. 9). Spectroscopic data for twelve members oflibrary 21{1-8, 1-12} are listed below.

Compound 21{2,2}. ¹H NMR (DMSO-d6) δ 9.3 (br, 2H), 8.04 (t, J=3.3 Hz,1H), 7.28 (m, 2H), 7.20 (m, 2H), 6.76 (m, 2H), 6.01 (m, 2H), 3.94 (t,J=4.1 Hz, 2H), 3.47 (d, J=7.1 Hz, 2H), 3.28 (q, J=4.0 Hz, 2H), 2.97-2.84(m, 4H), 2.70 (t, J=4.3 Hz, 2H), 2.32-2.29 (m, 1H), 2.11-2.05 (m, 2H),1.84-1.71 (m, 4H); ¹³C NMR (DMSO-d6) δ 172.5, 139.4, 128.6, 128.2,126.1, 120.5, 107.9, 53.6, 51.2, 45.8, 35.0, 25.9, 25.5.

Compound 21{3,7}. ¹H NMR (DMSO-d6) δ 9.21 (br, 1H), 8.50 (t, J=5 Hz,2H), 7.32 (t, J=4.5 Hz, 2H), 7.24 (t, J=4.5 Hz, 2H), 5.82-5.77 (m, 1H),5.03 (d, J=10.5 Hz, 1H), 4.98 (d, J=6.1 Hz, 1H), 4.26 (d, J=3.5 Hz, 2H),3.51 (d, J=7.1 Hz, 2H), 3.05-3.01 (m, 2H), 2.89 (q, J=6.6 Hz, 2H),2.47-2.44 (m, 1H), 2.05 (q, J=4.3 Hz, 2H) 1.93 (d, J=8.1 Hz, 2H),1.84-1.79 (m, 2H), 1.67-1.60 (m, 2H), 1.37 (q, J=4.5 Hz, 2H); ¹³C NMR(DMSO-d6) δ 172.7, 139.4, 138.0, 128.3, 127.1, 126.8, 115.3, 55.8, 51.1,41.9, 32.5, 25.9, 25.2, 22.7.

Compound 21{2,9} ¹H NMR (DMSO-d6) δ 8.03 (s, 1H), 7.30-7.27 (m, 2H),7.21-7.18 (m, 2H), 6.94-6.89 (m, 5H), 4.7 (s, 1H), 4.29 (dd, J=7.0, 1.1Hz, 1H), 3.05 (s, 2H), 2.71 (t, J=4.4 Hz, 2H), 2.35 (s, 1H), 1.89 (m,4H); ¹³C NMR (DMSO-d6) δ172.5, 139.4, 128.7, 128.3, 126.1, 121.8, 117.4,117.2, 68.0, 65.0, 55.8, 52.4, 51.7, 35.0, 25.9.

Compound 21{4,4} ¹H NMR (DMSO-d6) δ 9.47 (s, 1H), 8.01 (t, J=3.3 Hz,1H), 7.37-7.34 (m, 2H), 7.30-7.25 (m, 2H), 7.10 (d, J=5.0 Hz, 2H),0.6.84 (d, J=5.0 Hz, 2H), 3.72 (s, 3H), 3.57 (m, 2H), 3.34-3.31 (m, 5H),3.00-2.84 (m, 4H), 2.64 (t, J=4.4 Hz, 2H), 2.37-2.32 (m, 1H), 1.89-1.73(m, 3H); ¹³C NMR (DMSO-d6) δ 172.5, 157.7, 136.9, 131.2, 129.7, 128.8,126.9, 114.1, 113.7, 56.6, 55.1, 51.2, 34.2, 29.5, 25.9.

Compound 21{1,1}. ¹H NMR (DMSO-d6) δ 8.41 (t, J=3.5 Hz, 1H), 7.15 (d,J=5.1 Hz, 2H), 6.88 (d, J=5.1 Hz, 2H), 4.25-4.19 (m, 6H), 3.72 (s, 3H),3.01 (s, 2H), 1.92 (br, 4H), 1.24 (t, J=4.2 Hz, 3H); ¹³C NMR (DMSO-d6) δ172.5, 165.9, 158.2, 131.3, 128.5, 113.7, 61.9, 55.1, 41.4, 25.6, 13.9.

Compound 21{6,10}. ¹H NMR (DMSO-d6) δ 8.54 (t, J=3.5 Hz, 1H),0.7.78-7.72 (m, 2H), 7.69-7.57 (m, 4H), 7.50-7.44 (m, 3H), 7.37-7.31 (m,3H), 4.31-4.25 (m, 4H), 3.41 (d, J=7.1 Hz, 2H), 2.99-2.95 (m, 2H),2.50-2.47 (m, 1H), 1.97-1.80 (m, 4H); ¹³C NMR (DMSO-d6) δ 172.7, 139.9,138.8, 138.6, 133.3, 132.5, 129.0, 127.8, 126.9, 126.6, 57.7, 50.9,41.7, 25.8.

Compound 21{5,3}. ¹H NMR (DMSO-d6) δ 11.0 (s, 1H), 10.2 (s, 1H),7.62-7.57 (m, 3H), 7.51 (d, J=4.5 Hz, 2H), 7.38 (d, J=4.8 Hz, 2H), 7.25(s, 1H), 7.12-7.09 (m, 1H), 7.04-7.01 (m, 1H), 3.72 (d, J=7.1 Hz, 2H),3.14-3.11 (m, 2H), 3.03 (q, J=6.7 Hz, 2H), 2.66-2.60 (m, 1H), 2.09-186(m, 4H); ¹³C NMR (DMSO-d6) δ 171.9, 138.4, 136.3, 131.5, 126.6, 123.2,121.3, 121.1, 118.5, 118.2, 114.9, 111.6, 108.9, 56.1, 51.0, 25.8, 19.8.

Compound 21{8,12}. ¹H NMR (DMSO-d6) δ 8.05 (s, 1H), 7.87 (d, J=4.5 Hz,2H), 7.63 (d, J=4.5 Hz, 2H), 7.57 (d, J=4.2 Hz, 2H), 7.47-7.42 (m, 3H),7.36-7.33 (m, 1H), 7.27 (d, J=4.7 Hz, 2H), 4.98 (s, 4H), 3.52-3.49 (m,2H), 3.02-3.00 (m, 2H), 2.76 (t, J=4.3 Hz, 2H), 2.39 (s, 3H), 1.90 (br,4H).

Compound 21{5,11}. ¹H NMR (DMSO-d6) δ 9.2 (s, 1H), 8.04 (d, J=4.5 Hz,1H), 7.30 (s, 1H), 7.26 (d, J=5.7 Hz, 1H), 7.02 (d, J=5.0 Hz, 1H), 3.93(s, 1H), 3.51 (d, J=7.2 Hz, 2H), 3.06-3.02 (m, 2H), 2.93-2.78 (m, 4H),2.56-2.53 (m, 2H), 2.38-2.35 (m, 1H), 1.88-1.76 (m, 5H), 1.64-1.50 (m,3H), 0.90 (d, J=4.6 Hz, 6H); ¹³C NMR (DMSO-d6) δ 172.3, 138.4, 134.1,131.2, 130.9, 128.4, 118.6, 54.5, 51.1, 44.3, 34.3, 31.9, 27.9, 26.9,26.0, 25.9, 25.7, 22.1.

Compound 21{5,5}. ¹H NMR (DMSO-d6) δ 8.04 (d, J=4.5 Hz, 1H), 7.35-7.26(m, 4H), 7.04-6.99 (m, 4H), 4.33 (t, J=2.8 Hz, 2H), 3.94-3.92 (m, 1H),3.61 (d, J=7.2 Hz, 2H), 3.57 (s, 2H), 3.04-3.02 (m, 2H), 2.94-2.89 (m,1H), 2.87-2.78 (m, 2H), 2.56-2.53 (m, 1H), 2.40-2.37 (m, 1H), 1.90-1.84(m, 4H), 1.64-1.62 (m, 1H); ¹³C NMR (DMSO-d6) δ 172.3, 157.5, 138.4,134.1, 131.2, 130.9, 129.6, 128.4, 121.4, 118.6, 114.7, 62.0, 55.0,51.8, 44.3, 34.3, 27.9, 26.9, 25.9.

Compound 21{1,8}. ¹H NMR (DMSO-d6) δ 8.42 (t, J=3.4 Hz, 1H), 7.15 (d,J=5.1 Hz, 2H), 6.87 (d, J=5.2 Hz, 2H), 4.19 (d, J=3.3 Hz, 2H), 3.72 (s,3H), 2.94 (t, J=6.9 Hz, 2.84 (t, J=4.5 Hz, 1H), 2.74 (t, J=4.5 Hz, 1H),2.4 (m, 1H), 1.93-1.77 (m, 4H); ¹³C NMR (DMSO-d6) δ 171.6, 170.6, 169.5,130.3, 127.5, 112.7, 54.1, 50.9, 50.4, 40.4, 27.7, 27.4, 25.0.

Although the present invention has been described in detail inconnection with the above examples, it is to be understood that suchdetail is solely for that purpose and that variations can be made bythose skilled in the art without departing from the spirit of theinvention except as it may be limited by the following claims.

1. A compound having the formula:

wherein Rf is a fluorous group selected from the group consisting of aperfluorocarbon, a fluorohydrocarbon, a fluorinated ether or afluorinated amine having a plurality of carbon-fluorine bonds and havinga molecular weight less than 2500, n is an integer between 1 and 6, m is1, 2 or 3, Ra is an alkyl group or a halo-alkyl group and X is a halide,—N₃, —CN, RO—, NH₂O—, NHRO—, NR₂O—, RCO₂—, ROCO₂—, RNCO₂—, RS—, RC(S)O—,RCS₂—, RSC(O)S—, RSCS₂— RSCO₂—, ROC(S)O—, ROCS₂—, RSO₂—, RSO₃—, ROSO₂—,ROSO₃—, RPO₃—, ROPO₃—, an N-imidazolyl group, an N-triazolyl group, anN-benzotriazolyl group, a benzotriazolyloxy group, an imidazolyloxygroup, an N-imidazolinone group, an N-imidazolone group, anN-imidazolinethione group, an N-succinimidyl group, an N-phthalimidylgroup, an N-succinimidyloxy group, an N-phthalimidyloxy group,—ON═C(CN)R, or a 2-pyridyloxy group, wherein R is an alkyl group, ahaloalkyl group, an aryl group, a halo-aryl group, an alkyl-aryl group,a cyano-aryl group, or a nitro-aryl group.
 2. The compound of claim 1wherein X is a halide, —N₃, —CN, RO—, NR₂O—, RCO₂—, ROCO₂—, RS—,RC(S)O—, RCS₂—, RSC(O)S—, RSCS₂— RSCO₂—, ROC(S)O—, ROCS₂—, RSO₂—, RSO₃—,ROSO₂—, ROSO₃—, RPO₃—, ROPO₃—, an N-imidazolyl group, an N-triazolylgroup, an N-benzotriazolyl group, a benzotriazolyloxy group, animidazolyloxy group, an N-imidazolinone group, an N-imidazolone group,an N-imidazolinethione group, an N-succinimidyl group, an N-phthalimidylgroup, an N-succinimidyloxy group, an N-phthalimidyloxy group,—ON═C(CN)R, or a 2-pyridyloxy group, wherein R is an alkyl group, ahaloalkyl group an aryl group, a halo-aryl group, an alkyl-aryl group, acyano-aryl group, or a nitro-aryl group.
 3. The compound of claim 1wherein m is 1 or 2 and Ra is a C₁-C₆ alkyl group.
 4. The compound ofclaim 1 wherein the fluorous group has a molecular weight less than1,750.
 5. The compound of claim 4 wherein fluorous group is aperfluoroalkyl group.
 6. The compound of claim 1 wherein X is Cl, N₃ or—ON═C(CN)Ph.
 7. The compound of claim 1 wherein the fluorous taggingcompound includes at least 9 fluorine atoms.
 8. The compound of claim 1where Rf is a fluorous group selected from the group of C₂₋₁₅perfluoroalkyl groups, C₁₋₁₅ hydrofluoroalkyl groups, a fluorinatedether and a fluorinated amine.
 9. The compound of claim 8 wherein X is ahalide, —N₃, —CN, RO—, NR₂O—, RCO₂—, ROCO₂—, RS—, RC(S)O—, RCS₂—,RSC(O)S—, RSCS₂— RSCO₂—, ROC(S)O—, ROCS₂—, RSO₂—, RSO₃—, ROSO₂—, ROSO₃—,RPO₃—, ROPO₃—, an N-imidazolyl group, an N-triazolyl group, anN-benzotriazolyl group, a benzotriazolyloxy group, an imidazolyloxygroup, an N-imidazolinone group, an N-imidazolone group, anN-imidazolinethione group, an N-succinimidyl group, an N-phthalimidylgroup, an N-succinimidyloxy group, an N-phthalimidyloxy group,—ON═C(CN)R, or a 2-pyridyloxy group, wherein R is an alkyl, a haloalkylgroup an aryl group, a halo-aryl group, an alkyl-aryl group, acyano-aryl group, or a nitro-aryl group.
 10. The compound of claim 9wherein m is 1 or 2 and Ra is a C₁-C₆ alkyl group.
 11. The compound ofclaim 9 wherein fluorous group is a C₂₋₁₅ perfluoroalkyl group.
 12. Thecompound of claim 9 wherein X is Cl, N₃ or —ON═C(CN)Ph.
 13. The compoundof claim 9 wherein the fluorous tagging compound includes at least 9fluorine atoms.